Binge-like ethanol consumption increases corticosterone levels and neurodegneration whereas occupancy of type II glucocorticoid receptors with mifepristone is neuroprotective

ABSTRACT Excessive ethanol (EtOH) use leads to impaired memory and cognition. Using a rat model of binge‐like intoxication, we tested whether elevated corticosterone (Cort) levels contribute to the neurotoxic consequences of EtOH exposure. Rats were adrenalectomized (Adx) and implanted with cholesterol pellets, or cholesterol pellets containing Cort in order to achieve basal, medium, or high blood concentrations of Cort. Intragastric EtOH or an isocaloric control solution was given three times daily for 4 days to achieve blood alcohol levels ranging between 200 and 350 mg/dl. Mean 24‐hour plasma levels of Cort were ∼110 and ∼40 ng/ml in intact EtOH‐treated and intact control animals, respectively. Basal Cort replacement concentrations in EtOH‐treated Adx animals did not exacerbate alcohol‐induced neurodegeneration in the hippocampal dentate gyrus (DG) or the entorhinal cortex (EC) as observed by amino‐cupric silver staining. In contrast, Cort replacement pellets resulting in plasma Cort levels twofold higher (medium) than normal, or greater than twofold higher (high) in Adx‐Cort‐EtOH animals increased neurodegeneration. In separate experiments, pharmacological blockade of the Type II glucocorticoid (GC) receptor was initiated with mifepristone (RU38486; 0, 5, 15 mg/kg/day, i.p.). At the higher dose, mifepristone decreased the number of degenerating hippocampal DG cells in binge‐EtOH–treated intact animals, whereas, only a trend for reduction was observed in 15 mg/kg/day mifepristone‐treated animals in the EC, as determined by fluoro‐jade B staining. These results suggest that elevated circulating Cort in part mediates EtOH‐induced neurotoxicity in the brain through activation of Type II GC receptors. Excessive ethanol use leads to impaired memory and cognition. Using a rat model of binge‐like intoxication, we tested whether elevated corticosterone (Cort) levels contribute to the neurotoxic consequences of EtOH exposure. Rats were adrenalectomized (Adx) and implanted with cholesterol pellets, or cholesterol pellets containing Cort in order to achieve basal, medium, or high blood concentrations of Cort. Intragastric EtOH or an isocaloric control solution was given three times daily for 4 days to achieve blood alcohol levels ranging between 200 and 350 mg/dl.